NEUROPATHOLOGY CORE PROJECT SUMMARY/ABSTRACT The importance of human brain tissue in ADRD research cannot be overstated, both as a resource to explore and define novel molecular pathways, as well as a critical resource for animal researchers who wish to validate their findings in human tissue. The AMP-AD initiative recently launched by NIA is further validation of the importance of human brain tissue in defining disease-relevant pathways, and has resulted in numerous publications that have added to our evolving understanding of AD pathogenesis. The Columbia University ADRC Neuropathology (NP) Core has a long history of serving the wider ADRD research community?s need for well characterized human brain tissue, and we will continue this mission under this new P30 application. The chief function of the NP Core is to provide state-of-the-art diagnostic services, and to collect, maintain, and distribute optimally prepared brain samples to researchers at Columbia and throughout the world. The NP Core also has a responsibility to train and educate the next generation of neurodegenerative disease researchers and brain bankers. Finally, the NP Core will contribute to the investigation of the three pathways that are the scientific focus of this application. With regards to tissue banking and distribution, the NP Core has a well-established procedure for receiving and banking brains, and we will continue this protocol for this new P30 application. Upon death of a donor, one half brain is immersed in formalin and kept for thorough neuropathological evaluation, and the contralateral half is extensively dissected at the fresh state and processed to yield up to 150 blocks and pulverized aliquots of parenchyma. Our samples are barcoded and electronically tracked, which aids in organizing the samples, maintaining them safely, and ultimately speeds the selection of samples for research. With regards to education, the NP Core has a long-standing tradition of educating the next generation of neuroscientists and brain bankers, through weekly brain cutting, monthly clinicopathological conferences, and periodic hosting of visiting neuroscientists throughout the world (since 2001, our methodology has been fully or partially instituted at eight other academic sites). Finally, we will use the resources of the NP core to inform on the three AD-associated biological pathways. Specifically, we will use single-nucleus RNA-seq to ask the following questions: 1) What cell types express the three established genes that relate to the three pathways (i.e. TREM2, APOE, SORL1)?; 2) Is there regional variation in the cell types that express these three genes?, and 3) Does this expression pattern change during successive Braak stages?